DESCRIPTION (Applicant's Abstract): The goal of the Developmental Genome Anatomy Project (DGAP) is to identify genes critical in human development that are disrupted or dysregulated by balanced chromosomal rearrangements in humans with multiple congenital anomalies. Approximately 1 in 2000 newborns has an apparently balanced rearrangement, with a 6.1 percent risk for a serious congenital anomaly. These anomalies can include isolated defects ranging from cleft palate/lip, abdominal wall defects, limb defects, cardiac abnormalities or mental retardation, or they can occur as part of clinically recognizable syndromes. Of particular relevance is the fact that de novo structural abnormalities involving all chromosomes have been reported in association with congenital anomalies; it has been speculated that a significant number of such chromosomal breaks directly disrupt or dysregulate genes critical to specific molecular pathways. We propose to study individuals with multiple congenital anomalies and apparently balanced chromosomal rearrangements, with the aim of using balanced chromosomal rearrangements as signposts to identify these critical genes. The potential of DGAP will be greatly enhanced by rapidly evolving genomic resources including the complete human DNA sequence and an ordered FISH BAC map of the human genome. Collaborations established between cytogeneticists and clinical geneticists across the medical genetics community have been established to collect patient samples with a variety of developmental defects and balanced chromosomal rearrangements. Analysis of chromosomal breakpoints through FISH mapping studies will be used to identify single genomic clones containing relevant candidate sequences, and an online DGAP database is being created (Project 1). Molecular identification and analysis of candidate genes, as well as mutation studies in affected individuals will be the focus of subsequent studies (Project 2). Identification of expression patterns assessing tissue or temporal specificity will follow, as well as isolation of homologs in M. musculus and D. melanogaster (Project 3). Ultimately, transgenic animals will be used to study specific clones of interest to elucidate more fully their role in development (Project 3). DGAP constitutes a multi-laboratory and multi-institutional research endeavor which brings together the disciplines of clinical genetics, cytogenetics, molecular biology and developmental genetics to illuminate genes involved in fundamental pathways during human development.